Permanent suspension pharmaceutical dosage form

ABSTRACT

Permanent suspension dosage forms of drugs, particularly of the water-sensitive type, for administration without reconstitution are disclosed. The suspensions contain a drug dispersed in an anhydrous vegetable oil vehicle containing a saccharide as the suspending agent. These suspensions in dosage unit form exhibit long term stabilities, extended shelf lives, and excellent taste characteristics.

BACKGROUND OF THE INVENTION

a. Field of the Invention

This invention relates to permanent suspension dosage forms of watersensitive drugs particularly suitable for oral administration withoutreconstitution. These dosage forms have exhibited unique long termstabilites and extended shelf lives. They possess excellent tastecharacteristics, and bioavailabilities.

B. Prior Art

Commerical aqueous suspension of antibiotics for oral administrationhave limited shelf lives because of the instability of the antibiotic inaqueous media. For example, commerical ampicillin oral suspensions,after reconstitution with water according to manufacter's instructionswill decompose about 0.2% per day at 4° C. and 0.6% per day at 25° C.Therefore, these dosage forms must be marketed dry, as a powder, forreconstitution with water immediately prior to dispensing to thepatient.

U.S. Pat. No. 3,097,135 describes a prior art approach to overcomingthis instability problem by providing a method for the stabilization oferythromycin in an anhydrous emulsion for oral administration. A varietyof emulsifying agents and processing temperatures of 85°-90° C aredescribed.

West German Offenlegungsschrift No. 2,250,680 describes the preparationof stable suspensions suitable for antibiotics which employ a variety of"necessary agents", including an emulsifying agent, "in the properratio" to achieve a suspension alleged to be stable, although withoutany supporting data.

Oral pharmaceutical composition employing mono-, di- or triglycerides ofsaturated acids having 6 to 12 carbon atoms as "adsorption promotingagents" for a variety of drugs are described in Belgian Pat. No.807,312. The thrust of this patent is to facilitate thegastro-intestinal adsorption of the drug, thus, intensifying orpromoting its therapeutic effect. No stability data or shelf-lifecharacteristics of the resulting compositions are given.

It is an object of this invention to provide permanent suspensions ofdrugs dispersed in an anhydrous vehicle constituting a uniquestructurized suspension. The compositions of this invention do notrequire heat during manufacture, nor do they require emulsifying agentsto achieve commercially acceptable stability and exceptional shelf-life.

SUMMARY OF THE INVENTION

It has been found that stable suspensions suitable for oraladministration are provided by suspending a therapeutically effectiveamount of a water sensitive drug in an anhydrous vehicle comprising asugar and a vegetable oil, said sugar suitable, and present in an amountsufficient, to cause a suspension to form. Also constituting a novelembodiment of this invention is the foregoing anhydrous vehicle.

A preferred embodiment of this invention is a vegetable oil vehicle witha suitable pharmaceutically acceptable thickening agent, effective tothicken the oil, and a sugar. The water sensitive drug is dispersed inthe resulting structurized suspension. No heating is required to preparea stable suspension. Good stability of the water sensitive drug in suchpermanent suspension form results. Bioavailability equal to that of thecommercially available aqueous suspensions has been demonstrated.

Exemplary of such a preferred embodiment is a therapeutically effectiveamount of a drug, selected from the group consisting of aspirin,amoxicillin, ampicillin, amoxicillin in combination with probenecid, andampicillin in combination with probenecid suspended in an anhydrousvegetable oil vehicle comprising from about 5 to about 60% sucrose andfrom about 0.1 to about 5% silica thickening agent. The foregoingpercentages are by weight of total suspension which in unit dosage formcontains conventional pharmaceutically acceptable excipients selectedfrom preservatives, antioxidants, flavors and colors. Before bringing abatch unit dosage suspension to final volume or weight, conventionalconcentrations of selected pharmaceutical excipients can be introduced.

DETAILS OF THE INVENTION

Typically an oral unit dosage form of the permanent suspensions of theinvention contains the drug, (generally of the water-sensitive type),thickening agent, sugar, ie. saccharide, vegetable oil, preservative,antioxidant, flavoring, and color. Each of these ingredients isdiscussed in more detail hereinafter.

Although any drug which is stable in the presence of a vegetable oilvehicle can be employed as the pharmaceutically active component in thenovel suspensions of this invention, particular noteworthy advantagesare manifested in the cases of formulations incorporatingwater-sensitive drugs, and specifically those water-sensitive drugshaving a bitter taste. Antibiotics, clofibrate aspirin and disulfiramare exemplary of drugs which can advantageously be employed.Illustrative of the antibiotics are those of the penicillin family, suchas the penicillins (eg. penicillin V, penicillin G, penicillan K),ampicillin, amoxicillin, oxacillin, cloxacillin, flucloxacillin,dicloxacillin, phenethicillin, propicillin, carbenicillin, methicillinand other synthetic or semi-synthetic penicillins; the tetracyclinefamily, such as tetracycline, chlortetracycline, or oxytetracycline;other antibiotics, such as kitasamycin, erythromycin, thecephalosporins, griseofulvin, rapamycin, chloramphenicol; or antibioticsin combination with one or more drugs, including the foregoingrepresentative antibiotics. Representative of such combinations areamoxicillin or ampicillin in combination with probenecid, or withaspirin.

For convenience and to avoid undue prolix, the drugs set forth hereinare described by the appropriate generic name. As used herein, however,the generic name includes (in those cases where they exist) the freeacid or base (ie. amphoteric) form, the anionic salts with acids, suchas inorganic acids (eg. hydrochloric acid, sulfuric acid, etc.), thecationic salts with bases such as sodium hydroxide, potassium hydroxide,procaine, or benzathine, amides and esters such as the tartrate. Alsoincluded are the anhydrous and hydrated forms where applicable, eg.ampiclillin.

Although various sugars can be employed as a component of the novelpermanent suspensions of the invention, sucrose is highly preferred.Extrapolated room temperature stability studies of a sucrose-sesameoil-ampicillin system revealed an extrapolated shelf-life (30° C) forthis system to be greater than five years. When mannitol (chosen for itscomparable taste masking characteristics) was substituted for sucrose inthe same system the extrapolated shelf-life was not more than 1 year.Exemplary of the other saccharides (ie. mono-, di- or poly-) which canbe employed are lactose, fructose, glucose, mannitol, or sorbitol.

The sugar can be employed in any pharmaceutically acceptable form. Forexample, in the case of sucrose, it can be employed as sucrose, U.S.P.;pulverized sucrose or confectionary sucrose.

The vegetable oil vehicle can be any natural or syntheticpharmaceutically acceptable vegetable oil, such as peanut oil, soy beanoil, corn oil, sesame oil, cottonseed oil, acetylated glycerides, ethyloleate, mineral oil, mono- or di- fatty acid esters of polyethyleneglycols, or glyceryl mono-oleate. The oils comprise a mono-, di-, ortriglyceride, alone or in combination, prepared from saturated fattyacids. It is preferred that the oil be a glyceryl ester of a C₁₄ -C₂₂saturated and/or unsaturated fatty acids. Preferred vegetable oilvehicles are, peanut oil, coconut oil, corn oil, and sesame oil which isespecially preferred. Fatty acids having from about six to about 20carbon atoms can be employed.

Although the drugs incorporated in the permanent suspensions of thisinvention exhibit excellent stability, with shelf lives exceeding fiveyears in some cases, (as, for example, with ampicillin), it has beenfound that an exceptionally elegant suspension can be obtained by theincorporation of a silica agent. These suspensions exhibit excellentshelf lives, with minimal percent oil separation, and providepseudoplastic viscosity of the permanent suspension.

Various grades of silica available commercially can be employed.Exemplary are those available under the SYLOID brand name from W. R.Grace & Co., Davison Chemical Division, Baltimore, Maryland 21203; theCAB-O-SIL brand name from Cobot Corporation, Boston, Massachusetts; orthe aerosil name from Dow-Corning Corp., Midland, Michigan or Degussa,Frankfort, W. Germany.

It has been found that silica agents exhibiting certain parametersimpart exceptional characteristics to the novel suspensions of thisinvention. The preferred characteristics of the silica agent are an"oleophilicity" of about one, a slightly alkaline pH in water, and aparticle size range of 2 to 4 microns. ("oleophilicity" is defined asthe ratio between oil absorption lbs./100 lbs. and the surface area M²/gm., of the silica gelling agent). Maximum and effective thickening andminimum oil separation upon aging occurs with those silicas having anoleophilicity of about one. Especially preferred silica agents are thoseexemplified by SYLOID grades 266-86 and 244-68 (as defined in DavisonProduct brochure PA 59-371 entitled "Family of SYLOID Silicas at Work")including the following physical-chemical properties: An alkaline pH (5%aqueous slurry) of no higher than eight, preferably about 7.6; anoleophilicity (as herein defined) of 0.75 to 1.4 and preferably0.90-1.10, and a particle size density (gms./ml.) of about 0.55.

In preparing the stable suspensions of this invention in pharmaceuticalunit dosage form, minor amounts of conventional and commerciallyavailable pharmaceutical excipients (ie, acceptable, pharmaceuticalgrade preservatives, antioxidants, flavors and colors) can be employed,provided each is compatible with the drug-vehicle system involved.Exemplary of such excipients are preservatives selected from theparabens (eg. propylparaben), benzyl alcohol or phenol; antioxidantsselected from ascorbyl palmitate, butylated hydroxytoluene, butylatedhydroxyanisole or tertiary butyl hydroquinone; flavors selected fromimitation banana or chocolate (eg. 59.256/A or 57.328/A respectively,Firmenich, Inc., N.Y.), imitation orange (eg. V. 30795 InternationalFlavors and Fragrances, N.Y.).

The range of ingredients in the permanent suspension formulation of thisinvention can vary from about 5 to about 60 percent of the sugar, fromabout 0.1 to about 5.0 percent of the silica agent, a pharmaceuticallyeffective amount of the selected drug, conventional minor amounts (eg.less than about 5%) of pharmaceutical excipients, and the vegetable oilvehicle which constitutes the balance of the total suspension. Thepreferred amounts of sugar and silica agent range from about 20% toabout 40% and about 0.5% to about 1.5% respectively. (As used herein,all percentages are by weight based on total suspension unless otherwisestated.)

The preparation of the novel suspensions herein described is simple andstraight-forward. In general it involves the following sequences:

A. Add the sugar, in successive portions, to a portion of vegetable oilin a suitable blender and stir to suitably disperse and suspend thesystem.

B. Add silica (eg. SYLOID or CAB-O-SIL) agent and stir until dispersed.

C. Add drug and stir until a suspension is obtained

D. Optimally add pharmaceutical excipients (eg. preservative, flavor,dye, antioxidant) and stir for a few minutes. (Optional)

E. Add sufficient additional vegetable oil to bring the final weight ofthe batch to 100 parts by weight and stir to obtain a uniformsuspension.

The absence of a heating step is a unique feature of the process of thisinvention. The process is also unique in not requiring an emulsifying orantiprecipitation agent to achieve stable suspensions with minimal oilseparation. Furthermore, the process does not require the use of specialmixing equipment capable of a high degree of pulverization at criticaltemperatures. (Compare West German Offenlegungsschrift No. 2,250,680 ofMay 10, 1973, and Belgian Pat. No. 807,312, filed Nov. 14, 1973.)

The following examples demonstrate this invention:

EXAMPLES

                  Examples                                                        ______________________________________                                        1. Amoxicillin Permanent Suspension                                           ______________________________________                                        A. Formula for 25 mg/ml                                                       Amoxicillin Trihydrate                                                                           2.50 Gm.                                                   Sucrose, Powdered  20.00 Gm.                                                  CABOSIL            1.25 Gm.                                                   Seasame Oil q.s.   100.00 ml.                                                 Stability Data                                                                Storage Conditions Amoxicillin Recovered                                      ______________________________________                                        Initial            24.4 mg/ml                                                  3 days at 80° C                                                                          23.2                                                        7 days at 80° C                                                                          22.7                                                       10 days at 80° C                                                                          21.6                                                       14 days at 80° C                                                                          19.2                                                       30 days at 80° C                                                                          14.6                                                        3 days at 74° C                                                                          23.5                                                       14 days at 74° C                                                                          21.7                                                        7 days at 62° C                                                                          23.4                                                        2 months at 62° C                                                                        22.3                                                        2 months at 51° C                                                                        23.9                                                        3 months at 51° C                                                                        22.1                                                       12 months at 40° C                                                                        22.7                                                       12 months 30° C                                                                           23.3                                                       ______________________________________                                    

Based on these data, it is estimated that the formula will be stable forat least 3 years at room temperature.

    ______________________________________                                        B. Formula for 50 mg/Gm. (made in research laboratory)                        Amoxicillin Trihydrate                                                                           5.00 Gm.                                                   Sucrose, Powdered  27.50 Gm.                                                  SYLOID (266-86)    1.00 Gm.                                                   Citric Acid        0.01 Gm.                                                   Propyparaben       0.10 Gm.                                                   Tert. Butylhydroquinone                                                                          0.02 Gm.                                                   Imitation Chocolate                                                                              0.20 Gm.                                                   Cocoa              1.00 Gm.                                                   Sesame Oil, q.s.   100.00 Gm.                                                 Stability Data                                                                Storage Conditions Amoxicillin Recovered                                      ______________________________________                                        Initial            51.1 mg/Gm.                                                3 days at 80° C                                                                           46.5                                                       1 week at 80° C                                                                           36.5                                                       2 weeks at 80° C                                                                          15.8                                                       1 week at 74° C                                                                           45.4                                                       2 weeks at 74° C                                                                          38.7                                                       1 month at 74° C                                                                          20.8                                                       2 months at 74° C                                                                         14.0                                                       1 month at 62° C 46.2                                                  2 months at 62° C                                                                         43.5                                                       4 momths at 62° C                                                                         34.2                                                       6 months at 30° C                                                                         51.8                                                       ______________________________________                                    

Based on these data, it is estimated that the formula will be stable forat least 3 years at room temperature.

In a crossover 24-subject bioavailability study, Amoxicillin PermanentSuspension as described above was compared with a commercial AmoxicillinAqueous Suspension* (reconstituted with water according to the labelinstruction of the manufacturer,

    ______________________________________                                        Time in Hours                                                                            Drug Concentration in Serum, mcg/ml                                ______________________________________                                        After Oral Permanent          Aqueous                                         Administration                                                                           Suspension         Suspension                                      ______________________________________                                        0          0.00               0.00                                            0.5        3.00               4.89                                            1          5.45               6.26                                            1.5        5.08               4.69                                            2          3.86               3.34                                            3          1.82               1.69                                            4          0.83               0.77                                            5          0.37               0.33                                            6          0.15               0.13                                            8          0.02               0.00                                            ______________________________________                                    

The equivalency between these two dosage forms (i.e. Amoxil and 1.C.) isclearly demonstrated.

    ______________________________________                                        C. Formula for 50 mg/Gm. (made in production facility)                        Amoxicillin Trihydrate                                                                           5.00 Gm.                                                   Sucrose, Powdered  27.50 Gm.                                                  SYLOID (266-86)    1.00 Gm.                                                   Citric Acid        0.01 Gm.                                                   Propylparaben      0.10 Gm.                                                   Tert. Butylhydroquinone                                                                          0.02 Gm.                                                   Imitation Chocolate                                                                              0.20 Gm.                                                   Cocoa              1.00 Gm.                                                   Sesame Oil, q.s.   100.00 Gm.                                                 Stability Data                                                                Storage Conditions Amoxicillin Recovered                                      ______________________________________                                        Initial            47.0 mg/ml                                                 1 day at 80° C                                                                            43.9                                                       3 days at 80° C                                                                           40.5                                                       5 days at 74° C                                                                           45.1                                                       2 weeks at 62° C                                                                          44.4                                                       1 month at 62° C                                                                          45.9                                                       2 months at 51° C                                                                         46.4                                                       ______________________________________                                    

Based on these data, it is estimated that the formula will be stable forabout 3 years at room temperature.

D. tert. Butylhydroquinone can be eliminated from Formulation B withoutsignificantly altering the chemical stability of the product.

E. propylgallate can be used to substitute tert. butylhydroquinone inFormulation B without significantly altering the physical and chemicalstability of the product.

F. polysaccharides, disaccharides and monosaccharides, such as sorbitol,mannitol, lactose, glucose or fructose can be substituted for sucrose inFormulation B.

    __________________________________________________________________________    2. Ampicillin Permanent Suspension                                            __________________________________________________________________________    A. Formula for 50 mg/Gm. of Ampicillin                                        Ampicillin Trihydrate   51.7                                                  __________________________________________________________________________     Gm.                                                                          Sucrose, Powdered       35.00 Gm.                                             SYLOID (266-86)         0.75 Gm.                                              Imitation Chocolate     0.15 Gm.                                              Cocoa                   1.00 Gm.                                              Sesame Oil, q.s.        100.00 Gm.                                            Stability Data                                                                Storage Conditions      Ampicillin recovered                                  __________________________________________________________________________    Initial                 48.4 mg/Gm.                                           8 hr. at 80° C   42.1                                                  16 hr. at 80° C  35.4                                                  1 day at 80° C   26.7                                                  1 day at 74° C   41.3                                                  2 days at 74° C  33.7                                                  3 days at 74° C  22.1                                                  1 wk. at 62° C   53.8                                                  2 weeks at 62° C 52.5                                                  3 weeks at 62° C 47.9                                                  3 weeks at 30° C 49.1                                                  7 months at 30° C                                                                              51.7                                                  __________________________________________________________________________

Based on these data, it is estimated that the formula will be stable forat least 3 years at room temperature.

    ______________________________________                                        B. Formula for 100 mg/Gm.                                                     Ampicillin Trihydrate                                                                            10.0 Gm.                                                   Sucrose, Powdered  40.0 Gm.                                                   CABOSIL            1.0 Gm.                                                    Corn Oil, q.s.     100.0 Gm.                                                  Stability Data                                                                Storage Condition  Ampicillin Recovered                                       ______________________________________                                        Initial            90.2                                                        1 day at 80° C                                                                           33.0                                                        2 weeks at 62° C                                                                         75.7                                                       18 days at 51° C                                                                          88.7                                                        8 weeks at 51° C                                                                         80.9                                                       13 months at 40° C                                                                        82.5                                                       20 months at 40° C                                                                        82.1                                                       25 months at 40° C                                                                        71.3                                                       57 weeks at RT     91.6                                                       25 months at 30° C                                                                        82.5                                                       ______________________________________                                    

Based on these data, it is estimated that the formula will be stable forat least 3 years at room temperature.

    ______________________________________                                        C. Formula for 50 mg/ml.                                                      Ampicillin Trihydrate at 86%                                                                           5.87 Gm.                                             Sucrose, Powdered        27.50 Gm.                                            SYLOID (266-86)          1.00 Gm.                                             Propylparaben milled     0.10 Gm.                                             Tertiary butyl hydroquinone                                                                            0.02 Gm.                                             Citric Acid Anhydrous    0.01 Gm.                                             Imitation Chocolate      0.20 ml.                                             Cocoa                    1.00 Gm.                                             Sesame Oil, q.s.         100  ml.                                             ______________________________________                                    

Ampicillin permanent suspension as described in 2.C. (except thatimitation orange wonf was substituted for the chocolate and cocoa) wascompared with a Commercial Ampicillin Aqueous Suspension. (PENBRITIN,Ayerst, McKenna & Harrison, Ltd.). The equivalency between these twodosage forms in a crossover 18-subject bioavailability study was clearlydemonstrated.

    ______________________________________                                        Stability Data (2.C.)                                                         Storage Conditions  Ampicillin Recovered                                      ______________________________________                                        Initial             47  mg/ml                                                 1 day at 74° C                                                                             44.6                                                      2 days at 74° C                                                                            40.1                                                      7 days at 74° C                                                                            16.2                                                      1 week at 62° C                                                                            44.0                                                      ______________________________________                                    

Based on these data, it is estimated that the formula will be stable forabout 3 years at room temperature.

    ______________________________________                                        3. Aspirin Permanent Suspension                                               ______________________________________                                        A. Formula for 60 mg/Gm.:                                                     Aspirin              6.0 Gm.                                                  Sucrose, Powdered    27.5 Gm.                                                 SYLOID (266-86)      1.0 Gm.                                                  Sesame Oil, q.s.     100.0 Gm.                                                Stability Data                                                                Storage Conditions   Aspirin Recovered                                        ______________________________________                                        Initial              62.4 mg/Gm.                                              1 day at 80° C                                                                              54.1                                                     4 days at 80° C                                                                             41.3                                                     4 days at 74° C                                                                             47.5                                                     3 months at 62° C                                                                           56.8                                                     ______________________________________                                    

Based on these data, it is predicted that the formula will be stable forat least one year.

    ______________________________________                                        B. Formula for 60 mg./Gm.                                                     Aspirin              6.0 Gm.                                                  Sucrose, Powdered    27.5 Gm.                                                 SYLOID (266-86)      1.0 Gm.                                                  Glyceryl Mono-oleate, q.s.                                                                         100.0 Gm.                                                Stability Data                                                                Storage Conditions   Aspirin Recovered                                        ______________________________________                                        Initial              58.8 mg/Gm.                                              1 day at 80° C                                                                              47.6                                                     4 days at 80° C                                                                             38.2                                                     4 days at 74° C                                                                             44.9                                                     3 months at 62° C                                                                           54.8                                                     ______________________________________                                    

Based on these data, it is estimated that the formula will be stable forat least one year at room temperature.

    ______________________________________                                        C. Formula for 60 mg/Gm.                                                      Aspirin            6.00 Gm.                                                   Sucrose, Powdered  27.50 Gm.                                                  SYLOID (266-86)    1.00 Gm.                                                   Propylparaben      0.10 Gm.                                                   Ter. Butylhydroquinone                                                                           0.02 Gm.                                                   Citric Acid Anhydrous                                                                            0.01 Gm.                                                   Imitation Banana   0.35 Gm.                                                   Sesame Oil, q.s.   100.00 Gm.                                                 4. Amoxicillin Probenecid Suspension                                          ______________________________________                                        A. Formula for Amoxicillin 150 mg/ml and Probenecid 50 mg/ml:                 Amoxicillin Trihydrate                                                                       15.0 Gm.                                                       Probenecid     5.0 Gm.                                                        Sucrose, Powdered                                                                            20.00 Gm.                                                      SYLOID (266-90)                                                                              0.5 Gm.                                                        Propylparaben  0.1 Gm.                                                        Tertiary Butylhydroquinone                                                                   0.02 Gm.                                                       Citric Acid    0.01 Gm.                                                       Imitation Banana Flavor                                                                      0.2 ml.                                                        Sesame Oil, q.s.                                                                             100                                                            Stability Data                                                                               Amoxicillin  Probenecid                                        Storage Conditions                                                                           Recovered    Recovered                                         ______________________________________                                        Initial        143.3 mg/ml  51.1 mg/ml                                         8 hrs. at 80° C                                                                      137.2        --                                                16 hrs. at 80° C                                                                      138.7        --                                                 1 day at 80° C                                                                       131.8        48.8 - 3 days at 80° C 80.8 --              3 days at 74° C                                                                      129.9        51.9                                               5 days at 74° C                                                                      122.2        46.4                                               7 days at 74° C                                                                      110.9        49.8                                              17 days at 62° C                                                                      133.1        --                                                 5 weeks at 62°  C                                                                    120.7        46.0                                               7 weeks at 62° C                                                                     111.4        50.4                                              10 weeks at 62° C                                                                     84.9         50.0                                               3 months at 51° C                                                                    133.6        47.6                                              ______________________________________                                    

Based on these data, it is estimated that the formula will be stable forat least 3 years at room temperature.

    ______________________________________                                        B. Formula for Amoxicillin 100 mg/ml and Probenecid 50 mg/ml:                 ______________________________________                                        Amoxicillin Trihydrate                                                                       10.0 Gm.                                                       Probenecid     5.0 Gm.                                                        Sucrose, Powdered                                                                            25.0 Gm.                                                       SYLOID (266-90)                                                                              0.5 Gm.                                                        Propylparaben  0.1 Gm.                                                        Tertiary Butylhydroquinone                                                                   0.02 Gm.                                                       Citric Acid    0.01 Gm.                                                       Imitation Banana Flavor                                                                      0.2 ml.                                                        Sesame Oil, q.s.                                                                             100.0 ml.                                                                     Amoxicillin  Probenecid                                        Storage Conditions                                                                           Recovered    Recovered                                         ______________________________________                                        Initial        109.2 mg/ml  51.5 mg/ml                                         8 hrs. at 80° C                                                                      104.6        49.8                                              16 hrs. at 80° C                                                                      102.9        50.7                                               1 day at 80° C                                                                       101.8        52.6                                               2 days at 80° C                                                                      90           48.4                                               1 day at 74° C                                                                       105.7        50.9                                               3 days at 74° C                                                                      98.5         51.5                                               5 days at 74° C                                                                      93.2         54.3                                               7 days at 74° C                                                                      67.3         52.0                                               1 week at 62° C                                                                      107.2        50.3                                               2 weeks at 62° C                                                                     100.1        50.7                                               3 weeks at 62° C                                                                     93.8         56.1                                               4 weeks at 62° C                                                                     87.2         52.4                                               2 months at 51° C                                                                    112.7        58.3                                              ______________________________________                                    

Based on these data, it is estimated that the formula will be stable forat least 3 years at room temperature.

    __________________________________________________________________________    5. Amoxicillin Permanent Suspension                                           __________________________________________________________________________    A.    Formula for 50 mg/Gm.:                                                        Amoxicillin Trihydrate                                                                       5                                                              Saccharide*    27.50                                                                              Gm.                                                       SYLOID (266-86)                                                                              1.00 Gm.                                                       Tertiary Butyl Hydroquinone                                                                  0.02 Gm.                                                       Propylparaben  0.10 Gm.                                                       Citric Acid    0.01 Gm.                                                       Imitation Chocolate                                                                          0.20 Gm.                                                       Sesame Oil q.s.                                                                              100.00                                                                             Gm.                                                 __________________________________________________________________________     *Saccharides chosen for stability evaluation were sorbitol, mannitol,         lactose, glucose, fructose, or sucrose.?  ?                              

    B.    Stability Data                                                                     Amoxicillin Recovered mg/Gm. Expressed as                                     % initial                                                          __________________________________________________________________________    Storage                                                                       Conditions                                                                          Sorbitol                                                                           Mannitol                                                                           Lactose                                                                            Glucose                                                                            Fructose                                                                           Sucrose                                        __________________________________________________________________________    Initial                                                                             100  100  100  100  100  100                                            1 week at                                                                           Nil  Nil  Nil  Nil  Nil  69.2                                           80°                                                                    2 weeks at                                                                          89.3 96.3 101.3                                                                              76.4 64.7 --                                             51°                                                                    28 weeks                                                                            103.9                                                                              104.1                                                                              --   101.2                                                                              99.2 102.4                                          at RT                                                                         __________________________________________________________________________

Based on the 1 week data, sucrose is the preferred saccharide for theAmoxicillin Permanent Suspension.

Although the silica agents described are highly preferred, otherthixotropic agents can be employed to thicken the vegetable oil vehiclesof this invention. Exemplary are such agents selected fromcarbohydrates, proteins, cellulose derivatives, polysaccharides fromplant and marine sources, synthetic polymers, silicates and otherconventional thickners. Thickening of the vegetable oil vehicle can beachieved with effective amounts of calcium silicate, CARBOPOL 960 or 934(an ammonium salt or free acid form, respectively, of an acrylic acidpolymer with sucrose polyalkylether linkages, available from B. F.Goodrich Chemical Co.), Thixcin R and Thixcin E (Available from TheBaker Castor Oil Co., Bayonne, N.J.). Generally the effective amountsemployed fall below 5% of the total system on a weight basis.

In certain cases it may be desirable to prepare "sugar-free" permanentsuspensions. Such suspensions can be prepared by employing an effectiveamount of a silica agent of the type above described in place of thesugar in any of the suspensions of this invention. Such formulationsconstitute another embodiment of this invention.

Precoating the drug component of the suspensions herein described with anatural or synthetic macromolecule, eg. any pharmaceutically acceptablemacromolecule, or mixture thereof, compatible with said suspensions,constitutes another embodiment of this invention. Kitasamycin andCloxacillin are examples of drugs which can be formulated using thistechnique.

We claim:
 1. An anhydrous pharmaceutical vehicle suitable for oral administration of a water sensitive drug permanently suspended therein, said vehicle consisting essentially of:a. about 5 to about 60 percent by weight of a sugar suspending agent selected from the class consisting of sucrose, lactose, fructose, glucose, mannitol, and sorbitol; b. about 0.1 to about 5 percent by weight of a pharmaceutically acceptable silica thickening agent having a particle size of about 2 to about 4 microns, an alkaline pH (5 percent slurry in water) no higher than 8, and an oleophilicity of about 1; c. the remainder being a pharmaceutically acceptable vegetable oil comprising monoglyceride, diglyceride or triglyceride of a saturated fatty acid containing 14 to 22 carbon atoms or monoglyceride, diglyceride or triglyceride of an unsaturated fatty acid containing 14 to 22 carbon atoms.
 2. The vehicle of claim 1 wherein said water sensitive drug is selected from the group consisting of amoxicillin, ampicillin, amoxicillin in combination with probenecid, and ampicillin in combination with probenecid.
 3. The vehicle of claim 1 wherein the sugar suspending agent is sucrose.
 4. The vehicle of claim 1 wherein the vegetable oil is sesame oil.
 5. The vehicle of claim 1 wherein the sugar is present in amounts of about 20 to about 40 percent and the silica is present in amounts of about 0.5 percent to about 1.5 percent. 